Generation of optical vortex beams with bandwidth exceeding 550†nm using a helical fiber needle exhibiting strong mode coupling.

A strong-coupling helical fiber needle (HFN) is proposed and demonstrated for the realization of bandwidth-enhanced broadband optical vortex beam (OVB) generation. The HFN is based on a single mode fiber and operates at the dispersion-turning-point (DTP) of the lowest radial order of the cladding mode (i.e., LP11) but with a remarkably high mode coupling efficiency. By utilizing this novel, to the best of our knowledge, HFN, successful generation of the first-order OVB with an impressive bandwidth up to 556 nm at -10 dB and a center wavelength of ∼1570 nm has been achieved. This represents the broadest bandwidth demonstrated among all fiber grating-based OVB generators to date. The proposed HFN-based OVB generator exhibits a relatively compact size, ultra-wide bandwidth, and customizable center wavelength, making it highly promising for applications in optical vortex-based endoscopic imaging as well as particle detection and manipulation.

Design, synthesis, and antitumor activity evaluation of potent fourth-generation EGFR inhibitors for treatment of Osimertinib resistant non-small cell lung cancer (NSCLC).

Epidermal growth factor receptor (EGFR) is one of the most studied drug targets for treating non-small-cell lung cancer (NSCLC). However, there are no approved inhibitors for the C797S resistance mutation caused by the third-generation EGFR inhibitor (Osimertinib). Therefore, the development of fourth-generation EGFR inhibitors is urgent. In this study, we clarified the structure-activity relationship of several synthesized compounds as fourth-generation inhibitors against human triple (Del19/T790M/C797S) mutation. Representative compound 52 showed potent inhibitory activity against EGFRL858R/T790M/C797S with an IC50 of 0.55 nM and significantly inhibited the proliferation of the Ba/F3 cell line harboring EGFRL858R/T790M/C797S with an IC50 of 43.28 nM. Moreover, 52 demonstrated good pharmacokinetic properties and excellent in vivo efficacy. Overall, the compound 52 can be considered a promising candidate for overcoming EGFR C797S-mediated mutations.

Epidemiological and Clinical Characteristics of Neonatal Ureaplasma urealyticum Infection.

Purpose: To understand the epidemiology and clinical features of Ureaplasma urealyticum (UU) infection in hospitalized neonates due to vertical transmission from mother to child. Methods: Respiratory secretions were collected from neonates hospitalized in the neonatology department of the Maternal and Child Health Hospital of Hubei Province from July 2020 to June 2022, and PCR was used to detect UU-DNA in respiratory secretions. The neonates were divided into UU-positive and UU-negative groups, the epidemiological and clinical characteristics of two groups, were statistically analyzed. Results: A total of 7257 hospitalized neonates were included in this study, of whom 561 were UU positive and 6696 were UU negative, with a UU detection rate of 7.73%. The detection rate among female neonates was higher than male neonates, and the highest detection rate was found in the period from 1-7 days after birth; the detection rate was highest in spring and fall, and the lowest in winter, but the overall difference was not statistically significant (P>0.05). Compared with the UU-negative group, neonates in the UU-positive group were more likely to be preterm, have a lower birth weight, be delivered vaginally, and have maternal preterm rupture of membranes. In addition, neonates in the UU-positive group were more likely to be co-infected with pathogens and to have complications related to UU infections, which were all statistically significant (P<0.05). Conclusion: Neonatal UU infections are detected more frequently in female infants, with the highest detection rate occurring in 1-7 days after birth, and the most prevalent periods for infection being spring and fall. Vaginal delivery and premature rupture of membranes may lead to an increased risk of vertical UU transmission from mother to child, and UU infection is strongly associated with preterm labor, low birth weight, pathogen co-infection, and related complications.

Transcriptomic Signature of 3D Hierarchical Porous Chip Enriched Exosomes for Early Detection and Progression Monitoring of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a highly lethal malignant tumor, and the current non-invasive diagnosis method based on serum markers, such as α-fetoprotein (AFP), and des-γ-carboxy-prothrombin (DCP), has limited efficacy in detecting it. Therefore, there is a critical need to develop novel biomarkers for HCC. Recent studies have highlighted the potential of exosomes as biomarkers. To enhance exosome enrichment, a silicon dioxide (SiO2) microsphere-coated three-dimensional (3D) hierarchical porous chip, named a SiO2-chip is designed. The features of the chip, including its continuous porous 3D scaffold, large surface area, and nanopores between the SiO2 microspheres, synergistically improved the exosome capture efficiency. Exosomes from both non-HCC and HCC subjects are enriched using an SiO2-chip and performed RNA sequencing to identify HCC-related long non-coding RNAs (lncRNAs) in the exosomes. This study analysis reveales that LUCAT-1 and EGFR-AS-1 are two HCC-related lncRNAs. To further detect dual lncRNAs in exosomes, quantitative real time polymerase chain reaction (qRT-PCR) is employed. The integration of dual lncRNAs with AFP and DCP significantly improves the diagnostic accuracy. Furthermore, the integration of dual lncRNAs with DCP effectively monitors the prognosis of patients with HCC and detects disease progression. In this study, a liquid biopsy-based approach for noninvasive and reliable HCC detection is developed.

Association between Gut Microbiota and Biological Aging: A Two-Sample Mendelian Randomization Study.

Recent observational studies revealed an association between gut microbiota and aging, but whether gut microbiota are causally associated with the aging process remains unknown. We used a two-sample Mendelian randomization approach to investigate the causal association between gut microbiota and biological age acceleration using the largest available gut microbiota GWAS summary data from the MiBioGen consortium and GWAS data on biological age acceleration. We further conducted sensitivity analysis using MR-PRESSO, MR-Egger regression, Cochran Q test, and reverse MR analysis. Streptococcus (IVW, ß = 0.16, p = 0.0001) was causally associated with Bioage acceleration. Eubacterium (rectale group) (IVW, ß = 0.20, p = 0.0190), Sellimonas (IVW, ß = 0.06, p = 0.019), and Lachnospira (IVW, ß = -0.18, p = 0.01) were suggestive of causal associations with Bioage acceleration, with the latter being protective. Actinomyces (IVW, ß = 0.26, p = 0.0083), Butyricimonas (IVW, ß = 0.21, p = 0.0184), and Lachnospiraceae (FCS020 group) (IVW, ß = 0.24, p = 0.0194) were suggestive of causal associations with Phenoage acceleration. This Mendelian randomization study found that Streptococcus was causally associated with Bioage acceleration. Further randomized controlled trials are needed to investigate its role in the aging process.

HBV promotes its replication by up-regulating RAD51C gene expression.

Chronic hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC), pegylated-interferon-α(PEG-IFNα) and long-term nucleos(t)ide analogs (NUCs) are mainly drugs used to treat HBV infection, but the effectiveness is unsatisfactory in different populations, the exploration of novel therapeutic approaches is necessary. RAD51C is associated with DNA damage repair and plays an important role in the development and progression of tumors. Early cDNA microarray results showed that RAD51C expression was significantly increased in HBV-infected HCC cells, however, the relationship between HBV infection and abnormal expression of RAD51C has not been reported. Therefore, we conducted RT-PCR, western blot, Co-immunoprecipitation(Co-IP), and immunofluorescence(IF) to detect HBV-RAD51C interaction in RAD51C overexpression or interfering HCC cells. Our results showed that RAD51C and HBV X protein(HBX) produced a direct interaction in the nucleus, the HBV infection of HCC cells promoted RAD51C expression, and the increased expression of RAD51C promoted HBV replication. This indicated that RAD51C is closely related to the occurrence and development of HCC caused by HBV infection, and may bring a breakthrough in the the prevention and treatment study of HCC.

STAT3 palmitoylation initiates a positive feedback loop that promotes the malignancy of hepatocellular carcinoma cells in mice.

Constitutive activation of the transcription factor STAT3 (signal transducer and activator of transcription 3) contributes to the malignancy of many cancers such as hepatocellular carcinoma (HCC) and is associated with poor prognosis. STAT3 activity is increased by the reversible palmitoylation of Cys108 by the palmitoyltransferase DHHC7 (encoded by ZDHHC7). Here, we investigated the consequences of S-palmitoylation of STAT3 in HCC. Increased ZDHHC7 abundance in HCC cases was associated with poor prognosis, as revealed by bioinformatics analysis of patient data. In HepG2 cells in vitro, DHHC7-mediated palmitoylation enhanced the expression of STAT3 target genes, including HIF1A, which encodes the hypoxia-inducible transcription factor HIF1α. Inhibiting DHHC7 decreased the S-palmitoylation of STAT3 and decreased HIF1α abundance. Furthermore, stabilization of HIF1α by cyclin-dependent kinase 5 (CDK5) enabled it to promote the expression of ZDHHC7, which generated a positive feedback loop between DHHC7, STAT3, and HIF1α. Perturbing this loop reduced the growth of HCC cells in vivo. Moreover, DHHC7, STAT3, and HIF1α were all abundant in human HCC tissues. Our study identifies a pathway connecting these proteins that is initiated by S-palmitoylation, which may be broadly applicable to understanding the role of this modification in cancer.

Corrigendum: The prospective outcome of the Monkeypox outbreak in 2022 and characterization of monkeypox disease immunobiology.

[This corrects the article DOI: 10.3389/fcimb.2023.1196699.].

Acoustic quasi-periodic bioassembly based diverse stem cell arrangements for differentiation guidance.

Arrangement patterns and geometric cues have been demonstrated to influence cell function and fate, which calls for efficient and versatile cell patterning techniques. Despite constant achievements that mainly focus on individual cells and uniform cell patterns, simultaneously constructing cellular arrangements with diverse patterns and positional relationships in a flexible and contact-free manner remains a challenge. Here, stem cell arrangements possessing multiple geometries and structures are proposed based on powerful and diverse pattern-building capabilities of quasi-periodic acoustic fields, with advantages of rich patterns and structures and flexibility in structure modulation. Eight-fold waves' interference produces regular potentials that result in higher rotational symmetry and more complex arrangement of geometric units. Moreover, through flexible modulation of the phase relations among these wave vectors, a wide variety of cellular pattern units are arranged in this potential, such as circular-, triangular- and square-shape, simultaneously. It is proved that these diverse cellular patterns conveniently build human mesenchymal stem cell (hMSC) models, for research on the effect of cellular arrangement on stem cell differentiation. This work fills the gap of acoustic cell patterning in quasi-periodic patterns and shows promising potential in tissue engineering and regenerative medicine.

Full C-band covered and DWDM channelized high channel-count all-fiber orbital-angular-momentum mode generator based on the fiber gratings.

To generate the orbital-angular-momentum (OAM) modes at multiple wavelengths, which exactly fit with the dense-wavelength-division-multiplex (DWDM) channel grids, is important to the DWDM-based OAM mode-division-multiplex (MDM) fiber communication system. In this study, a full C-band covered and DWDM channelized OAM mode generator is firstly proposed and experimentally demonstrated, which is realized especially by using a broadband helical long-period fiber grating (HLPG) combined with a phase-only sampled multichannel fiber Bragg grating (MFBG). As a proof-of-concept example, the DWDM channelized two complementary 51-channel OAM mode generators have been successfully demonstrated, each of which has a channel spacing of 100 GHz (∼0.8 nm), an effective bandwidth of ∼40 nm, a high azimuthal-mode conversion efficiency of 90%, and high uniformities in both inter- and intra-channel spectra as well. To the best of our knowledge, this is the first time for proposal and experimental demonstration of such a high channel-count and DWDM channelized first-order OAM mode (l = 1) generator, which can also be used for multichannel higher-order OAM mode generation as long as the utilized HLPG is capable of generating a broadband higher-order OAM mode. The proposed device has potential applications to DWDM-based OAM fiber communications, OAM comb lasers, OAM holography, and OAM sensors as well.

Association between systemic immune-inflammation index and chronic obstructive pulmonary disease: a population-based study.

BACKGROUND: The Systemic Immune-Inflammation Index (SII) is a quantitative measurement of the systemic immune-inflammatory response in the human body. The SII has been shown to have prognostic value in various clinical settings, including critical illness, sepsis, and cancer. Its role in chronic obstructive pulmonary disease (COPD) remains unclear and requires further investigation. METHODS: We analyzed demographic data from 16,636 participants in the National Health and Nutrition Examination Survey. Logistic regression analysis was performed to assess the correlation between COPD, lung function, chronic respiratory symptoms and SII. We used Cox proportional hazards (PH) model to analyze the relationship between SII and mortality in COPD patients and healthy individuals. We used propensity score matching (PSM) method to match the COPD population with similar baseline levels with the normal population to further analyze the correlation between SII and COPD. RESULTS: We recruited 16,636 participants, ages 40 and above, for the study. A multivariable logistic regression analysis revealed that a higher SII level was independently associated with an elevated likelihood of COPD (Odds Ratio (OR) = 1.449; 95% Confidence Interval (CI): 1.252-1.676, P < 0.0001) after controlling for all other factors. Results of subgroup analysis showed a significant positive correlation between SII and COPD in different age groups, gender, Body Mass Index, smoking status, and those with a history of hypertension. The SII index had positive correlation with COPD after PSM (OR = 1.673; 95%CI: 1.443-1.938). After full adjustment, an increase in the SII is associated with a higher all-cause mortality rate. The hazard ratio (HR) with a 95% CI in the general population, COPD patients, and healthy individuals are 1.161 (1.088, 1.239), 1.282 (1.060, 1.550), and 1.129 (1.055, 1.207), respectively. CONCLUSIONS: Higher SII levels are linked to higher prevalence of COPD. COPD patients with a higher SII levels have a higher risk of all-cause mortality. Additional large-scale, long-term studies are necessary to confirm these results.

The prospective outcome of the monkeypox outbreak in 2022 and characterization of monkeypox disease immunobiology.

A new threat to global health re-emerged with monkeypox's advent in early 2022. As of November 10, 2022, nearly 80,000 confirmed cases had been reported worldwide, with most of them coming from places where the disease is not common. There were 53 fatalities, with 40 occurring in areas that had never before recorded monkeypox and the remaining 13 appearing in the regions that had previously reported the disease. Preliminary genetic data suggest that the 2022 monkeypox virus is part of the West African clade; the virus can be transmitted from person to person through direct interaction with lesions during sexual activity. It is still unknown if monkeypox can be transmitted via sexual contact or, more particularly, through infected body fluids. This most recent epidemic's reservoir host, or principal carrier, is still a mystery. Rodents found in Africa can be the possible intermediate host. Instead, the CDC has confirmed that there are currently no particular treatments for monkeypox virus infection in 2022; however, antivirals already in the market that are successful against smallpox may mitigate the spread of monkeypox. To protect against the disease, the JYNNEOS (Imvamune or Imvanex) smallpox vaccine can be given. The spread of monkeypox can be slowed through measures such as post-exposure immunization, contact tracing, and improved case diagnosis and isolation. Final Thoughts: The latest monkeypox epidemic is a new hazard during the COVID-19 epidemic. The prevailing condition of the monkeypox epidemic along with coinfection with COVID-19 could pose a serious condition for clinicians that could lead to the global epidemic community in the form of coinfection.

Valve-Adjustable Optofluidic Bio-Imaging Platform for Progressive Stenosis Investigation.

The clinical evidence has proven that valvular stenosis is closely related to many vascular diseases, which attracts great academic attention to the corresponding pathological mechanisms. The investigation is expected to benefit from the further development of an in vitro model that is tunable for bio-mimicking progressive valvular stenosis and enables accurate optical recognition in complex blood flow. Here, we develop a valve-adjustable optofluidic bio-imaging recognition platform to fulfill it. Specifically, the bionic valve was designed with in situ soft membrane, and the internal air-pressure chamber could be regulated from the inside out to bio-mimic progressive valvular stenosis. The developed imaging algorithm enhances the recognition of optical details in blood flow imaging and allows for quantitative analysis. In a prospective clinical study, we examined the effect of progressive valvular stenosis on hemodynamics within the typical physiological range of veins by this way, where the inhomogeneity and local enhancement effect in the altered blood flow field were precisely described and the optical differences were quantified. The effectiveness and consistency of the results were further validated through statistical analysis. In addition, we tested it on fluorescence and noticed its good performance in fluorescent tracing of the clotting process. In virtue of theses merits, this system should be able to contribute to mechanism investigation, pharmaceutical development, and therapeutics of valvular stenosis-related diseases.

Human papillomavirus genotypic characteristics of 60,685 subjects under age-expansion vaccination of the nine-valent human papillomavirus vaccine: A cross-sectional study.

BACKGROUND: Human papillomavirus (HPV) vaccination is a key initiative to promote the WHO global strategy to accelerate the elimination of cervical cancer, and this study aimed to investigate the current status of HPV infection and genotypic characteristics of the population under the impact of age-expansion of nine-valent HPV vaccination policy in China. METHODS: The clinical data of 60,685 subjects who were admitted in the Renmin Hospital of Wuhan University and underwent HPV genotyping from January 2017 to October 2022 were retrospectively analyzed. RESULTS: The total number of positive HPV genotyping in the included population was 10,303, with a positivity rate of 17.0 %. The HPV positivity rate in the male and female populations increased slowly year by year, with a higher rate of positivity in men (32.7 %) than in women (16.7 %) (P < 0.001). HPV was predominantly single infection in all populations, with higher prevalence of high-risk HPV than low-risk HPV in females, while low-risk HPV infection was predominant in the male population. The age distribution of female subjects infected with HPV, with HPV52 as the most common type, showed a bimodal pattern. As for HPV infected male subjects, HPV6 was the main type, and there was no bimodal age distribution. The expanded age vaccination of the nine-valent HPV vaccine will result in 42.4 % efficiency of vaccine protection for 49.9 % of age-eligible women. If the nine-valent HPV vaccine were open to males in China, it would reduce HPV infections in men by 56.4 %. CONCLUSIONS: The HPV positivity rate in the population remains high and tends to increase, and the age-expansion of the nine-valent HPV vaccine would contribute to reducing the threat of disease caused by HPV infection for age-eligible women. Moreover, attention should be paid to enhancing HPV screening in males and opening up vaccination when appropriate.

ß-Glucan Induces Training Immunity to Promote Antiviral Activity by Activating TBK1.

Many studies have shown that ß-glucan induces a trained immune phenotype in innate immune cells to defend against bacterial and fungal infections. The specific mechanism involves cellular metabolism and epigenetic reprogramming. However, it is unclear whether ß-glucan plays a role in antiviral infection. Therefore, this study investigated the role of trained immunity induced by Candida albicans and ß-glucan in antiviral innate immunity. It showed that C. albicans and ß-glucan promoted the expression of interferon-ß (IFN-ß) and interleukin-6 (IL-6) in mouse macrophages triggered by viral infection. In addition, ß-glucan pretreatment attenuated the pathological damage induced by the virus in mouse lungs and promoted the expression of IFN-ß. Mechanistically, ß-glucan could promote the phosphorylation and ubiquitination of TANK Binding Kinase 1 (TBK1), a key protein of the innate immune pathway. These results suggest that ß-glucan can promote innate antiviral immunity, and this bioactive material may be a potential therapeutic target for antiviral treatment.

Antibiotic-induced gut bacteria depletion has no effect on HBV replication in HBV immune tolerance mouse model.

Commensal microbiota is closely related to Hepatitis B virus (HBV) infection. Gut bacteria maturation accelerates HBV immune clearance in hydrodynamic injection (HDI) HBV mouse model. However, the effect of gut bacteria on HBV replication in recombinant adeno-associated virus (AAV)-HBV mouse model with immune tolerance remains obscure. We aim to investigate its role on HBV replication in AAV-HBV mouse model. C57BL/6 mice were administrated with broad-spectrum antibiotic mixtures (ABX) to deplete gut bacteria and intravenously injected with AAV-HBV to establish persistent HBV replication. Gut microbiota community was analyzed by fecal qPCR assay and 16S ribosomal RNA (rRNA) gene sequencing. HBV replication markers in blood and liver were determined by ELISA, qPCR assay and Western blot at indicated time points. Immune response in AAV-HBV mouse model was activated through HDI of HBV plasmid or poly(I:C) and then detected by quantifying the percentage of IFN-γ+/CD8+ T cells in the spleen via flow cytometry as well as the splenic IFN-γ mRNA level via qPCR assay. We found that antibiotic exposure remarkably decreased gut bacteria abundance and diversity. Antibiotic treatment failed to alter the levels of serological HBV antigens, intrahepatic HBV RNA transcripts and HBc protein in AAV-HBV mouse model, but contributed to HBsAg increase after breaking of immune tolerance. Overall, our data uncovered that antibiotic-induced gut bacteria depletion has no effect on HBV replication in immune tolerant AAV-HBV mouse model, providing new thoughts for elucidating the correlation between gut bacteria dysbiosis by antibiotic abuse and clinical chronic HBV infection.

Co-delivery of Cas9 mRNA and guide RNAs edits hepatitis B virus episomal and integration DNA in mouse and tree shrew models.

With 296 million chronically infected individuals worldwide, hepatitis B virus (HBV) causes a major health burden. The major challenge to cure HBV infection lies in the fact that the source of persistence infection, viral episomal covalently closed circular DNA (cccDNA), could not be targeted. In addition, HBV DNA integration, although normally results in replication-incompetent transcripts, considered as oncogenic. Though several studies evaluated the potential of gene-editing approaches to target HBV, previous in vivo studies have been of limited relevance to authentic HBV infection, as the models do not contain HBV cccDNA or feature a complete HBV replication cycle under competent host immune system. In this study, we evaluated the effect of in vivo codelivery of Cas9 mRNA and guide RNAs (gRNAs) by SM-102-based lipid nanoparticles (LNPs) on HBV cccDNA and integrated DNA in mouse and a higher species. CRISPR nanoparticle treatment decreased the levels of HBcAg, HBsAg and cccDNA in AAV-HBV1.04 transduced mouse liver by 53%, 73% and 64% respectively. In HBV infected tree shrews, the treatment achieved 70% reduction of viral RNA and 35% reduction of cccDNA. In HBV transgenic mouse, 90% inhibition of HBV RNA and 95% inhibition of DNA were observed. CRISPR nanoparticle treatment was well tolerated in both mouse and tree shrew, as no elevation of liver enzymes and minimal off-target was observed. Our study demonstrated that SM-102-based CRISPR is safe and effective in targeting HBV episomal and integration DNA in vivo. The system delivered by SM-102-based LNPs may be used as a potential therapeutic strategy against HBV infection.

Senotherapeutics: An emerging approach to the treatment of viral infectious diseases in the elderly.

In the context of the global COVID-19 pandemic, the phenomenon that the elderly have higher morbidity and mortality is of great concern. Existing evidence suggests that senescence and viral infection interact with each other. Viral infection can lead to the aggravation of senescence through multiple pathways, while virus-induced senescence combined with existing senescence in the elderly aggravates the severity of viral infections and promotes excessive age-related inflammation and multiple organ damage or dysfunction, ultimately resulting in higher mortality. The underlying mechanisms may involve mitochondrial dysfunction, abnormal activation of the cGAS-STING pathway and NLRP3 inflammasome, the role of pre-activated macrophages and over-recruited immune cells, and accumulation of immune cells with trained immunity. Thus, senescence-targeted drugs were shown to have positive effects on the treatment of viral infectious diseases in the elderly, which has received great attention and extensive research. Therefore, this review focused on the relationship between senescence and viral infection, as well as the significance of senotherapeutics for the treatment of viral infectious diseases.